Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide , 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR -/- ) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice ( P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions ( P < 0.0001); HDL cholesterol and PON were inversely correlated ( P < 0.0001). After feeding WD + 6F: i ) intact 6F was detected in small intestine (but not in plasma); ii ) small intestine LPA was decreased compared with WD + EV ( P < 0.0469); and iii ) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions ( P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.